Traceless Ligation of Cysteine Peptides Using Selective Deselenization

Metanis, Norman; Keinan, Ehud; Dawson, Philip E.

doi:10.1002/anie.201001900

Cited by 189 publications

(208 citation statements)

References 63 publications

(53 reference statements)

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“…Just as the pioneering synthetic work of Sir John Cornforth enabled the careful investigation of the mechanisms of enzyme catalysis, the programmed construction of homogeneous peptide and protein targets using the tools afforded by chemical synthesis will no doubt prove an invaluable resource for understanding the intricate relationship between protein structure and function. Madanin-1 (30)(31)(32)(33)(34)(35)(36)(37)(38)(39)(40)(41)(42)(43)(44)(45)(46) Madanin-1 (49-60)…”

Section: Discussionmentioning

confidence: 99%

“…Madanin-1 (1-27) Chimadanin (22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35)(36)(37)(38)(39)(40) Chimadanin Chimadanin (1-19)…”

Section: Discussionmentioning

confidence: 99%

“…Notably, the overall synthetic logic of Garner's aldehyde as a common starting point for the synthesis of functionalized amino acids for use in ligation chemistry has also been exploited for the preparation of a b-selenol derivative of phenylalanine. [35] This building block was successfully utilised in the construction of peptides using chemoselective ligationdeselenization chemistry, [36] a related field that has been the subject of recent reviews. [5o,12b] …”

Section: Synthesis Of Thiol-derived Amino Acids Through Nucleophilic mentioning

confidence: 99%

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Synthetic Amino Acids for Applications in Peptide Ligation–Desulfurization Chemistry

Malins

Payne

2015

Aust. J. Chem.

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Native chemical ligation is a powerful tool for the convergent assembly of homogeneous peptide and protein targets from unprotected peptide fragments. The method involves the chemoselective coupling of a peptide thioester with a peptide bearing an N-terminal cysteine (Cys) residue and is mediated by the nucleophilic Cys thiol functionality. A widely adopted extension of the technique for the disconnection of protein targets at alanine (Ala) ligation junctions has been the application of post-ligation desulfurization protocols for the mild removal of the Cys thiol moiety. Recently, attention has turned to the construction of synthetic amino acid building blocks bearing suitably positioned b-, g-, or d-thiol ligation auxiliaries with a view to expanding the scope of the ligation-desulfurization manifold. To date, several thiol-derived amino acids have been prepared, greatly increasing the generality and flexibility of chemoselective ligation technologies for the chemical synthesis of diverse protein targets. This review will highlight the current synthetic approaches to these important amino acid building blocks.

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Section: Discussionmentioning

confidence: 99%

“…Madanin-1 (1-27) Chimadanin (22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35)(36)(37)(38)(39)(40) Chimadanin Chimadanin (1-19)…”

Section: Discussionmentioning

confidence: 99%

Section: Synthesis Of Thiol-derived Amino Acids Through Nucleophilic mentioning

confidence: 99%

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Synthetic Amino Acids for Applications in Peptide Ligation–Desulfurization Chemistry

Malins

Payne

2015

Aust. J. Chem.

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“…Such methods are not ideal for the generation of analogs (30)(31)(32)(33). It was recognized that enhancement of the power of chemical synthesis for such objectives, including that of hPTH itself, could be accomplished by extending the reach of the underlying elegant concept of NCL (4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17). To this end, we report a pleasing and encouraging example wherein these recent findings have been pooled such that the molecule hPTH can be conveniently assembled from small synthetic peptide fragments.…”

mentioning

confidence: 94%

“…(2,3). However, given the relative scarcity of cysteine residues in nature, a clear impetus arises for the realization of new NCL capabilities (4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17).…”

mentioning

confidence: 99%

Application of the logic of cysteine-free native chemical ligation to the synthesis of Human Parathyroid Hormone (hPTH)

Shang

Tan

Danishefsky

2011

Proc. Natl. Acad. Sci. U.S.A.

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The power of chemical synthesis of large cysteine-free polypeptides has been significantly enhanced through the use of nonproteogenic constructs which bear strategically placed thiol groups, enabling native chemical ligation. Central to these much expanded capabilities is the specific, radical-induced, metal-free dethiolation, which can be accomplished in aqueous medium. Anticipating this type of problem, our laboratory (9, 11, 14, 17) and others (5-7, 10) have developed strategies by which to accomplish ligation at a range of noncysteine amino acid residues. The logic of our approach is outlined in Fig. 1. The N-terminal peptide, D, to be ligated is equipped with an N-terminal sulfurbearing amino acid surrogate, A, itself prepared by synthesis and coupled, by a suitable method, to the peptide B. In this way, N-terminal ligation candidate D is ready for coupling with C-terminal acyl donating peptide C (usually a thioester). Ligation product E can be maintained as such, thereby affording a specifically placed thiol group in a nonnatural context. Theoretically, de-thiolation of E will produce F wherein the "R" group had been governed by the synthetically derived A. In principle, the strategy shown in Fig. 1 is of universal scope.Studies using a variety of model peptides have demonstrated the fragment-coupling capability of the cysteine-free strategy. Here, in this paper, we seek to examine the general applicability of this strategy to the total synthesis of cysteine-poor proteins. Human Parathyroid Hormone (hPTH) is chosen to serve as a model molecule because of its representativeness in terms of amino acid composition and its therapeutic value. hPTH is a biological messenger that is secreted by the parathyroid glands as a peptide containing 84 amino acids (18,19). Upon binding to its receptor, hPTH can enhance the concentration of calcium (Ca 2þ ) in the blood (20). Because of their important physiological roles, hPTH and one of its fragments, hPTH (1-34), are now given (by subcutaneous injection) for the treatment of hypoparathyroidism and osteoporosis in men, as well as for postmenopausal women at high risk of fracture (21-23). Not unlike most other hormone drugs, the recombinant hPTH therapeutics have very short half-lives in the human body and need to be administered at least once a day (24, 25). The need for continuous daily subcutaneous injection is an obvious disadvantage which serves to compromise use of the hormone. Clearly, the production of more stable forms of hPTH, where "pharmacolability" is attenuated without undercutting biological activity, would be of great interest (26). It is also of interest to interrogate the consequences of employing nonproteogenic inserts (27). While this goal can be accomplished by cleverly designed recombinant methods, chemical synthesis could well be more convenient for servicing the initial production of probe structures for such structure-activity relationship (SAR) evaluations (28,29). Previously, the chemical synthesis of hPTH required either the solid phase synthes...

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Amide‐Forming Ligation Reactions

2019

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One of the long‐standing pursuits of synthetic organic chemists is the development of chemical methods for the synthesis of peptides and proteins as tools for understanding biological processes and providing therapeutic solutions to human diseases. The advent of chemoselective ligation reactions for the chemical synthesis of peptides and proteins has enabled synthetic chemists to realize this long‐held dream. In an amide‐forming ligation reaction, two uniquely placed functional groups within the peptide allow peptide or protein segments to be joined in a chemoselective manner with an amide bond. In this chapter, some of the early methods based on principles of the capture/rearrangement strategy for ligation of peptides are catalogued, followed by some of the most versatile and well‐established contemporary methods for the preparation of linear/cyclic peptides and proteins such as the native chemical ligation (NCL) and the α‐ketoacid–hydroxylamine (KAHA) ligation. The chapter concludes with some of the most promising new generation ligation methods such as the potassium acyltrifluoroborate–hydroxylamine (KAT) ligation. The tremendous progress in the past two decades in the development of several ligation methods that rely on a pair of unique functional groups is set to expand the horizons of fully functional proteins and multi‐protein assemblies that are purely synthetically prepared. Although contemporary ligation reactions do not match the speed and efficiency at which proteins are assembled in biological systems, the repertoire of chemoselective amide‐forming ligation methods has already enabled synthetic protein chemistry to surpass biology in terms of chemical and structural diversity.

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Traceless Ligation of Cysteine Peptides Using Selective Deselenization

Cited by 189 publications

References 63 publications

Synthetic Amino Acids for Applications in Peptide Ligation–Desulfurization Chemistry

Synthetic Amino Acids for Applications in Peptide Ligation–Desulfurization Chemistry

Application of the logic of cysteine-free native chemical ligation to the synthesis of Human Parathyroid Hormone (hPTH)

Amide‐Forming Ligation Reactions

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